Islam, Md Asiful
(2018)
Elucidation of clinical and laboratory features, comorbidity risks, treatment options and molecular pathophysiology of antiphospholipid syndrome (APS) patients.
Masters thesis, Universiti Sains Malaysia.
Abstract
Antiphospholipid syndrome (APS) is a systemic autoimmune disease
characterised by the presence of circulating antiphospholipid antibodies (aPLs) such
as lupus anticoagulant (LA), anticardiolipin (aCL) and anti-β2-glycoprotein I (β2-GPI)
antibodies to phospholipid binding proteins. Although the disease has been in
existence for approximately 35 years, the diagnostic criteria, risk factors, pathogenesis,
genetic aspects, treatment strategies are poorly understood and have yet to be fully
developed. In this study, the clinical and laboratory features, genetic risk factors,
comorbidity risks, molecular pathophysiology and optimal treatment strategy of APS
patients are explored. Human peripheral blood mononuclear cell (PBMC)-derived
high-quality and integrity RNA extraction and purification method was optimised
(centrifugal speed: 14000 rpm + spin time: 75 seconds + DNase treatment + Ribolock
RNase inhibitor + RNA clean-up) which could be used to send APS patients’ RNA for
RNA-Seq. In quest of APS patients, two studies were conducted. Firstly, on a familial
primary APS cases from Sarawak, Malaysia, patients however became seronegative
following long warfarin therapy. Another one with APS subjects from Hospital
Universiti Sains Malaysia (HUSM) were retrospectively investigated by exploring the
clinical, laboratory and treatment strategies. High occurrence of pregnancy morbidity,
as well as some unusual clinical features such as persistent dysfunction of liver and
kidneys; menorrhagia and ovarian cyst were observed. The use of medium-intensity
warfarin was successful in preventing thrombosis recurrence. Additionally, since theHUSM patients were unwilling to participate in this study, we were unable to send the
RNA samples for RNA-Seq to BGI. A systematic review with bioinformatic analyses
was conducted to identify the genetic risk factors in thrombotic APS subjects where
16 genes were significantly associated with thrombosis affecting mostly the blood
coagulation pathway and the immune system related to APS. Overall, three systematic
reviews and meta-analyses were conducted to determine the influence of aPLs in
patients with migraine, epilepsy and dementia without autoimmune disease as
compared to controls, where aPLs were significantly comorbid with the said
manifestations. Therefore, the neurologic features were early clinical manifestations
before the development of full-blown APS. A single Cochrane systematic review was
developed to explore the optimum treatment strategy for thrombotic APS subjects,
where, moderate-intensity warfarin was superior than high-intensity warfarin. Overall,
a comprehensive study exploring the clinical and laboratory features, genetic risk
factors, comorbidity risks, molecular pathophysiology and optimal treatment strategy
of APS patients was successfully established.
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